Individuals vary widely in their capacity to deliberate on the potential adverse consequences of their choices before they act. Highly impulsive people frequently make rash, destructive decisions, and impulsivity is one of the most compelling markers of vulnerability for the development of drug addiction. Importantly, impulsive traits are heritable, state-independent, and temporally stable developmental predictors of addiction risk, suggesting that they reflect underlying causal (i.e. genetic) risk factors. Given that the costs associated with substance abuse have been estimated to reach nearly $500 Billion/year, understanding the pathophysiological mechanisms through which such factors act to influence impulsivity and addiction susceptibility represents a critical goal for scientific investigation. Te long-term objective of our research is to define the precise neurobiological pathways that translate causal risk factors into deleterious decision-making biases and manifestly impulsive behavior. To that end, we have recently reported several findings suggesting a novel systems-level biological mechanism that may be critical in determining individual differences in impulsivity: reduced midbrain dopamine (DA) autoreceptor control over striatal DA release. First, individuals with high levels of impulsivity show lower midbrain D2-like autoreceptor levels as measured by Positron Emission Tomography (PET) with the D2/D3-selective tracer 18F-fallypride. Second, the magnitude of DA released within the striatum following administration of the stimulant drug d-Amphetamine (AMPH) was dramatically increased in individuals with high levels of impulsivity. Finally, midbrain D2-like autoreceptor levels inversely predicted the magnitude of AMPH-induced striatal DA release (which, in turn, positively predicted drug craving), and causal modeling demonstrated that the impact of lower midbrain autoreceptor levels on impulsivity was due to the associated dysregulation of striatal DA release. However, several critical questions remain, which will be addressed by scanning 16 participants with [18F]fallypride and a measure of DA synthesis capacity, [18F]fDOPA. First, we will examine the generalizability of DA circuit dysregulation to distinct forms of impulsive behavior. Participants will also be assessed on behavioral measures of impulsivity that relate to two distinct subcomponents: impulsive action and impulsive choice. This will permit us to determine the selectivity of relationships among objective behavioral measures of these distinct facets of impulsivity and presynaptic DA dysfunction. Second, we will elucidate the specific biochemical mechanism underpinning DA circuit dysregulation. By employing a novel multi-tracer PET approach that enables us to measure both midbrain D2 autoreceptors and striatal DA synthesis, we are able to test the hypothesis that diminished midbrain DA autoreceptor control leads to enhanced striatal DA transmission in impulsivity by dysregulating striatal DA synthesis. Finally, we will assess the implications of this dysregulation for current models of compulsive reward-seeking in addiction. Current influential models of striatal dysfunction in addiction emphasize the role of aberrant reward learning processes in the development of substance abuse, and they imply a facilitation of such maladaptive learning in individuals who have greater phasic DA responses to rewards. We will use model-based fMRI during an instrumental learning task to test the hypothesis that impulsivity is associated with potentiated reinforcement learning, and to determine if individual differences in presynaptic DA function (PET) predict DA-dependent striatal reinforcement learning signals (fMRI). Overall, this project utilizes a multi-level (brain chemistry, brain function, personality, cognition, and behavior) analytical approach to discover specific systems-level neurobiological mechanisms through which a heritable addiction susceptibility factor acts to put individuals at risk. By obtaining a fundamental understanding of the relationships between impulsivity, mesostriatal DA circuit function, and reinforcement learning in healthy young adults, we lay the foundation for future studies in patients and unaffected relatives. PUBLIC HEALTH RELEVANCE: Impulsivity is a robust risk factor for the development of substance use disorders. This proposal aims to test hypotheses about the specific neurobiological mechanisms that lead to individual differences in impulsivity. This work will form the basis of a translational research program that is centered on the development of novel interventions to prevent and treat substance use disorders.